The Bcl-2 family is a group of anti-apoptotic and pro-apoptotic proteins that regulate cell death. This regulation is determined by these proteins forming homodimer or heterodimer complexes with other members of the Bcl-2 family. When anti-apoptotic members form heterodimers with pro-apoptotic members cell death is inhibited. However, when pro-apoptotic members form homo or heterodimers with each other, cell death is induced. These protein complexes form primarily on the mitochondria. The pro-apoptotic complexes lead to mitochondrial changes in membrane potential, production of reactive oxygen species (ROS) and release of proteins from the mitochondria. These events lead to induction of cell death.
The Bcl-2 Nineteen Kilodalton Interacting Protein 3 (BNIP3) is a pro-apoptotic Bcl-2 family member that induces cell death independent of caspase activation and release of mitochondrial cytochrome c (5,8). It does require changes in mitochondrial membrane potential (Δψm) and production of reactive oxygen species (ROS) to induce cell death (5,11). BNIP3 contains a PEST domain that targets BNIP3 for degradation, a putative BH3 domain conserved among Bcl-2 family members, a conserved domain (CD) conserved between C. elegans and humans, and a TM domain that targets BNIP3 to the mitochondria essential for BNIP3-induced cell death (12,15). Hypoxic regions within tumors express high levels of BNIP3 (7,10). However, it is unclear what function BNIP3 plays in hypoxic regions of tumors where tumor cells remain viable. Malignant gliomas are one of the most aggressive tumors in cancer with tumor hypoxia limiting responses to multimodality therapy, including radiation and chemotherapy (1,16).